TAU is a protein with the ability to bind- and consequently stabilise and define-microtubule structure and function in neurons. The binding of TAU to microtubules is regulated by phosphorylation of TAU; several TAU phosphorylation sites and their corresponding kinases have been identified which control phosphorylation status of TAU and consequently modulate the affinity of TAU-binding to microtubules.
Tauopathies are characterised by insoluble aggregates or polymers of hyperphosphorylated TAU which are formed by self-polymerisation of TAU monomers.
An important aspect of the TAU aggregation is its associated cytotoxicity, which reduces neuronal integrity and functionality and ultimately resulting in disease symptoms. A direct role of TAU in disease onset has been established unequivocally by the elucidation of familial mutations in TAU, which appear to be responsible for a very early and sometimes aggressive form of tauopathy. Such mutations comprise changes in the amino acid sequence of TAU that—directly or indirectly promote neurotoxic aggregation.
Alzheimer's disease is the best known of these, where TAU protein is deposited within neurons in the form of neurofibrillary tangles (NFTs). They were first described by the eponymous Alois Alzheimer in one of his patients suffering from the disorder.
Currently used treatments for tauopathies, including Alzheimer's disease, offer only symptomatic benefit without impacting the underlying neurodegeneration.
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Treatments aimed to suppress cytotoxic TAU misfolding and/or aggregation, in order to delay or halt the progression of disease, are presently not available. Thus there is a need for new treatments that target the underlying molecular mechanism of noxious TAU misfolding and/or aggregation in order to reduce neuronal cell death and/or degeneration in patients suffering from tauopathies such as Alzheimer's disease (AD).